1. Field of the Invention
The present invention relates to indwelling medical articles, such as catheters, which may also be flushed or coated with a microbial-inhibiting pharmaceutical preparation. The invention also relates to pharmaceutical preparations useful in maintaining catheter patency and preventing infection. Methods of using the pharmaceutical preparation of the invention in the management and maintenance of a vascular catheter are also related to the present disclosure.
2. Background of the Related Art
Indwelling medical devices including vascular catheters have become essential in the management of hospitalized or chronically ill patients. Unfortunately, vascular catheters have become the major source for hospital-acquired sepsis. Hence, the benefit derived from indwelling medical devices such as vascular catheters is often upset by infectious complications. Thrombotic occlusions of the lumen of central venous catheters (CVC) is another complication that will often lead to the removal of catheters.
The current standard care of catheters includes flushing the lumen of the catheter with heparin. However, heparin has no antimicrobial activity. Thus, infections, as well as thrombotic occlusion, continue to occur frequently despite the prophylactic use of heparin flushes. Knowledge of the pathogenesis and microbiology of central venous catheter-related infections is essential in order to provide effective prevention for this problem. Three essential factors must be considered in controlling for catheter colonization by infectious microbes. The first is controlling the availability of microorganisms that adhere to the inert catheter surface. Such microorganisms typically include such staphylococci and candida. The second is control of the production slimy polysaccharide known as fibrous glycocalyx, by adherent microbial organisms. Production of the glycocalyx is essential for the adherence and integrity of these organisms. The third is control of the formation of the thrombin sheath by the host, which acts to engulf the catheter. The thrombin sheath provides the microorganisms a sticky substrate for enhanced adherence to the catheter, and thus, continued colonization and infection at the catheter site. The present inventors herein disclose an M-EDTA solution unique in its ability to inhibit all three of these essential conditions, and thus provide effective methods for controlling catheter-related infection and onset thereof.
Staphylococcus epidermidis and S. aureus account for 75% of CVC related infections. Candida species account for another 10% to 15% of such infections. The use of antistaphylococcal antibiotics to prevent these infections has been found to reduce CVC related bacterial infections, but only at the expense of the occurrence of higher rates of fungal (Candida) infections. The fibrous glycocalyx material produced by staphylococci and Candida helps these organisms adhere and stick to catheter surfaces, thus exacerbating the problem of eliminating these types of infections after they have become established. These microbial biofilm layers are made of a fibrous glycocalyx material primarily polysaccharide in nature. The protective sheath provided by the glycocalyx at the infected site effectively prevents the elimination and treatment of these infections. Preparation effective for destroying such a glycocalyx would, therefore, provide a solution to treating established catheter infections where a glycocalyx has already been allowed to form.
Compositionally distinct glycocalyx material is produced by a variety of different organisms. For example, the glycocalyx produced by Hymenolepis diminuta is reportedly eliminated upon treatment with 0.02 M-EDTA or 3M KCl.sup.12. However, the particular glycocalyx of Hymenolepis diminuta (tapeworm) is compositionally mostly proteins.sup.12, which is distinct from the material of the glycocalyx typical of those organisms that colonize and cause catheter infection. For example, the glycocalyx of several staphylococcus species comprise primarily polysaccharides with only low to nondeductible levels of protein.sup.13 (Tojo et al. at pg. 716, Table 1). Glycocalyx of microorganisms common to catheter infection are thus compositionally distinct from the organic composition of glycocalyx of such organisms as the tapeworm, Hymenolepis diminuta. A pharmaceutical preparation effective for reducing or eliminating glycocalyx of infectious microorganisms typically associated with catheter colonization and infection has yet to be identified.
Infectious microorganisms will typically embed themselves in the protective layer of the glycocalyx, thus providing a shield or hiding place that protects staphylococci and fungi from the activity of phagocytic cells. An agent or composition that would dissolve or prevent biofilm formation of these clinically important pathogens would thus provide a major breakthrough in the prevention of the typical catheter-related Staphylococcal and Candida infections that plague humans.
There has also been observed to be a correlation between thrombogenesis and infection. Essentially, indwelling vascular catheters get engulfed by a fibrin sheath that subsequently acts to cover the internal and external surfaces of a catheter. This fibrin sheath provides such organisms as Staphylococci and Candida, with an enhanced adherence capacity to the catheter surface. Unlike these particular microbes gram-negative bacilli do not adhere well to fibrin and fibronectin. A composition that halted fibrin formation would thus be particularly useful in halting the colonization of these microbes at indwelling catheter sites.
Intraluminal colonization through a catheter hub also constitutes a prelude to catheter-related infections and septicemias in long-term CVC. The inventors study presented herein of 359 long-term CVC patients (all of which were studied by quantitative catheter culture) demonstrates that CVC's with positive cultures as well as matched negative controls evidenced colonization (as quantitated by EM) and biofilm formation of the internal surface at least twice greater than that of external surface with catheters that stayed longer than 10 days in place. This data is from nontunneled, noncuffed percutaneous CVC. For tunneled CVCs (Hickman/Broviac) and ports, internal colonization was even more prominent. The development of an anticoagulant pharmaceutical preparation effective against staphylococci, fungi, and polysaccharide-rich glycocalyx formation would thus provide a solution to the treatment and elimination of thrombogenesis and the septicemia associated with long-term CVC.
EDTA is a well known anticoagulant used in blood collection tubes. It is also well known to have an antibacterial and antistaphylococcal effect (alone or in combination).sup.1-3. Root.sup.9 even compared to the efficacy of EDTA for use with vascular catheters as an antibacterial agent to heparin alone and a vancomycin-heparin preparation in vitro. While those investigators found EDTA to be bacteriocidal, no remedy or suggestion of how the microbial glycocalyx of a device-related infection could be eliminated was observed or described.
Although glycopeptide antibiotics (vancomycin and teicoplanin) are active against staphylococci in vitro and in tissue, they are not active against adherent staphylococci embedded in a biofilm layer, such as glycocalyx. While flushing with such agents may acutely destroy these microorganisms, the risk of rapid development of tolerant and resistant strains in the patient being treated makes this a contraindicated procedure in most cases. In addition, patients developing such vancomycin-tolerant or resistant strains bacteremias would be left without an antibiotic that could be used therapeutically.
Based on all of the above, the ideal prophylactic agent for catheter maintenance would both inhibit or eliminate the formation of polysaccharide-rich glycocalyx of such microorganisms as well as the staphylococci and fungi leading to the prevention of infection at a catheter surface.
It is an object of the invention to provide both an anti-staphylococcal and antifungal (anti-Candida) active agent effective against free-floating as well as adherent organisms embedded in biofilm, as well as to provide an anticoagulant agent and/or method that would prevent and alter/dissolve a polysaccharide-rich fibrous glycocalyx biofilm layer. Such a pharmaceutical agent would optimally provide an anticoagulant that would prevent thrombotic occlusion of the catheter lumen as well as thrombin formation that is the substrate for catheter infection. Additional objects of the invention include providing an agent that could be given intraluminally without a toxicity concern to humans and would provide a method that would kill adherent staphylococci and Candida. Such methods would preferably not be the same agent a clinician would use therapeutically (such as Vancomycin, Ampho B, or Azoles).
The present invention demonstrates that a mixture of minocycline/disodium EDTA (referred to as M-EDTA) does fulfill all of the listed objects.